Recent findings from the applicant's laboratories have demonstrated that decreases in CSF HIV-1 RNA concentration are strongly associated with improvement in neuropsychological test performance. These results provide further evidence for the role of HIV-1 viral load in the pathogenesis of AIDS dementia complex (ADC). The general goal of the collaborative research proposed is to define the role of MHC class I- restricted, anti-HIV-1 specific CD8+ cytotoxic T lymphocyte (CTL) responses in the control of HIV-1 replication within the CNS. Studies are proposed to test the working hypothesis that HIV-associated cognitive impairment is due to loss of control of HIV-1 replication within the CNS, that this loss of control is a consequence of viral escape from CTL responses, and that viral escape from immune control results in selection for unique strains of HIV-1 within the CNS of patients with ADC. The project will be conducted as an integrated and coordinated collaboration between investigators at the University of Hawaii and the University of Washington. The applicant component of the project will focus on characterizing HIV-1-specific CTL responses in the CNS of HIV-1 infected subjects, and determining whether changes in epitotic sequences of CNS-derived HIV-1 strains affect recognition of such epitopes, cognitive dysfunction, and CSF HIV-1 viral load. The hypotheses to be tested in both components are closely interrelated as are the experimental designs, and will allow for the complementary expertise of the investigations to be applied in a maximally productive and mutually beneficial way. The collaboration will also provide ample opportunities for students and fellows at the University of Hawaii to obtain training in the basic neuroscience techniques to be implemented in the conduct of this research efforts. The results of the proposed research will be relevant to understand the role of MHC class 1-restricted, anti-HIV-specific CD8+ CTL in controlling HIV-1 RNA viral load within the CNS, and will contribute to understanding the relationship between CSF HIV-1 viral load and the pathogenesis of AIDS dementia complex.